Vascular endothelial cells (ECs) line the internal surface of all blood vessels and are essential for vascular development and homeostasis. The de novo generation of blood vessels, known as vasculogenesis, is driven by the proliferation, migration and networking of endothelial progenitor cells. Subsequently, sprouting angiogenesis and intussusceptive angiogenesis drive new blood vessel formation from existing vessels, which is responsible for the expansion of vascular system. In the adult, the endothelium is normally quiescent, but angiogenesis can occur in response to stimuli. Physiological angiogenesis is associated with wound healing, post-ischemic tissue restoration and the menstrual cycle, while pathological angiogenesis is associated with numerous diseases, including cancer, age-related macular degeneration (AMD), diabetic retinopathy and atherosclerosis. Major breakthroughs have been made in the last decades regarding the cellular and molecular mechanism of angiogenesis. Vascular endothelial growth factor (VEGF) has been established as a major growth factor for ECs. Anti-angiogenic therapy, such as anti-VEGF antibodies, has shown efficacy in treating wet AMD and some cancers. However, in many cases the efficacy of anti-angiogenic therapy is still limited, suggesting complex mechanisms of angiogenesis. This necessitates a thorough mechanistic investigation of angiogenesis and the development of novel and alternative therapeutic approaches.
It is now established that up to 90% of the human genome is transcribed, and the majority of these transcripts are non-coding RNAs (ncRNAs) that do not encode proteins. ncRNAs can be classified as short noncoding RNAs such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and other classic ncRNAs. miRNAs include a group of small noncoding RNAs sized ˜22 nucleotides that play important regulatory functions in numerous physiological and pathological processes, including angiogenesis. lncRNAs represent a large group of long (typically >200 nt) noncoding RNAs, whose function is still largely enigmatic. A small number of well-studied lncRNAs have given us important clues about their biological function. lncRNAs have been shown to play key roles in diverse processes including genomic imprinting, cell cycle regulation and cell identity determination. Dependent on their subcellular localizations, lncRNAs may play a cis-acting regulatory function on nearby genes, regulate chromatin-modification through interacting with other factors, or regulate protein translation or miRNA function in the cytoplasm.
Several lncRNAs have been implicated in cardiovascular biology. The lateral plate mesoderm-specific lncRNA Fendrr has been shown to be required for proper heart and body wall development, and the lncRNA Braveheart (Bvht) is essential for cardiomyocyte lineage commitment. A recent study showed that overexpression of a cardiac-5 specific lncRNAMhrt was able to protect against pathological hypertrophy in mice. The expression, regulation and function of lncRNAs in vasculature is largely unknown. A recent characterization of lncRNAs in human umbilical vein ECs (HUVECs) identified an lncRNA named metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) that is highly expressed in HUVECs. MALAT1 functions to tip the balance from EC proliferation to migration and is required for vessel growth in vivo. RNA sequencing of human coronary smooth muscle cells (SMCs) has identified 31 unannotated lncRNAs, one of which is a vascular SMC- and EC-enriched lncRNA called SENCR, which functions to inhibit the migration of VSMCs. Another lncRNA, lncRNA-p21, functions to repress proliferation and induce apoptosis of VSMCs in vitro and in vivo, and is downregulated in atherosclerotic plaques of ApoE−/− mice and coronary artery tissues of human coronary artery disease patients. Overall, the role of lncRNAs in angiogenesis, especially human angiogenesis, is largely unknown.